News of the grant comes as UAlbany prepares to mark the second International Myotonic Dystrophy Awareness Day on Sept. 15, which will be commemorated in the Capital Region with green lights illuminating the Capitol, Empire State Plaza, SUNY and Alfred E. Smith buildings and UAlbany campus.
Myotonic dystrophy (abbreviated DM) affects muscle tissue, but also the heart, eyes and brain. Symptoms include myotonia (an inability to relax muscles), muscle wasting and muscle weakness. Patients can also experience lethargy, cataracts and glucose intolerance. Vision, speech, digestion and cognitive function also are often impaired.
“The symptoms of myotonic dystrophy are extremely varied — in terms of body systems affected, age of disease onset and symptom severity,” says Andrew Berglund, director of the College of Arts and Sciences’ RNA Institute and a co-principal investigator on the grant. “This complexity makes diagnosis challenging. And while myotonic dystrophy is familiar within the neurological community, it is largely unknown among general practitioners. This is why it often takes up to 8-10 years to reach a DM diagnosis; many doctors simply do not recognize the signs.”
[Listen to an interview with Berglund on UAlbany’s Engagement Ring podcast.]
Berglund has partnered with interdisciplinary researchers from across the country and the world to advance myotonic dystrophy research centered at UAlbany. He and his colleagues at the RNA Institute are developing new drugs to target myotonic dystrophy at the molecular level.
“DM patients are prescribed drugs to treat individual symptoms — some take dozens every day — but these drugs do not address the genetic root of the problem. Our team is working to target the disease itself, not the symptoms. Our previous work has revealed compounds that show great promise, and this grant will allow us to continue creating and testing new compounds.”
How myotonic dystrophy takes hold
Myotonic dystrophy is caused by “repeat expansion” — a type of genetic mutation that is also responsible for diseases like Huntington’s Disease and ALS.
A “repeat” is when a small section of the genetic code occurs multiple times in a row in the DNA. Repeats are common in our genome, yet typically occur no more than 20-30 times in a region and don’t typically change size. In people affected by a repeat expansion disease, this repetition grows and expands — up to tens to thousands of times in the same region of the genome— disrupting important processes in the cell.
“When repeat expansions are made into RNA, we get what is called toxic RNA,” explains John Douglas Cleary, a co-principal investigator on the grant and a collaborative staff scientist at the RNA Institute. “This toxic RNA pulls in proteins from within the cell, like a magnet dropped into a pile of metal filings. When these proteins are stuck to the toxic RNA, they can’t do their normal jobs to support critical functions throughout the body. This is how the disease affects so many systems.”
Searching for a cure
The RNA Institute team’s focus is on “small molecules” — compounds small enough to directly enter cells and target specific processes happening within them. The team is synthesizing novel compounds designed to target toxic RNA and reduce the effects of repeat expansion — a process called RNA rescue. The team’s ultimate goal is to develop a drug that can be delivered through an oral tablet and reach all organs in the body including the heart, muscles and brain.
Berglund explains, “Myotonic dystrophy is systemic, so while certain areas of the body may be more affected than others at different points in time, the disease is everywhere. If we can make a drug that stops or reduces the toxic RNA, this will address the problem throughout the body. Instead of treating one symptom at a time, this approach hopefully would address all symptoms everywhere.”
Compound creation begins in the digital world. First, the team creates computer models of promising compounds which they test against toxic RNA using a simulation. Compounds that prove effective are then synthesized and tested on a series of live cells. They start with fast-growing engineered cells that express the toxic RNA of myotonic dystrophy. Compounds that are successful at reducing toxic RNA without harming healthy RNA are tested in skin and muscle cells generously donated by people affected by DM. Those compounds that do well with muscle cells are administered to mice. At this stage, the team can assess effects of the compounds on symptoms that more closely match what happens in patients, like myotonia. So far, the team has tested thousands of compounds via computer simulation and cell line testing. About a dozen have made it to mouse trials.
“Each stage of testing gets us closer to a clinical trial in human patients,” Cleary explains. “At every stage, we also pay keen attention to safety and toxicity. If a compound shows signs of an off-target effect, we go back to our computational scientists and medicinal chemists to determine why this might be happening and what needs to be changed to fix the problem.
“This intensive iteration is critical to ensure that only compounds that are safe and effective are advancing to mice, and then eventually onto people. The process is extremely time and resource intensive — and is why funding, like this new grant from NIH, is so critically needed.”
Despite its relatively low profile, “the myotonic dystrophy research community is small but tremendously dedicated,” Berglund says. “In fact, many of the people working on the disease have personal connections to the research, including friends and family members affected by DM.
Visions for the future
At the RNA Institute, scientists are working to create a hub of research, training, and education to raise awareness of the disease, help medical practitioners better detect symptoms, and advance research toward treatments.
“Our vision is to continue to grow our capacity, both in infrastructure and people, and establish the New York Myotonic Dystrophy Center to further solidify and coalesce efforts to fight this disease,” Berglund says.
UAlbany is quickly becoming an important epicenter of DM research. The latest funding from NIH’s National Institute of Neurological Disorders and Stroke comes on top of $865,000 in generous support from the Canada-based Marigold Foundation toward creation of a myotonic dystrophy research center at UAlbany and $1 million in federal funding secured by U.S. Rep. Paul Tonko earlier this year.
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